The introduction of invasive stimuli, such as parasitic, bacterial or viral infections, or neoplastic cells, induce significant metabolic changes in the susceptible host. If serious, the changes may eventually disrupt normal homeostatic mechanisms, both locally and systemically, leading to the depletion of host energy stores advancing to wasting (Cachexia), tissue damage, multiple organ system failure, shock and death.
Until recently, clinicians believed that the systematic patterns were primarily due to actions of the invasive agents themselves. However, it is now known that the invasive stimuli cause the host to generate various cytokines, the combined actions of which cause most of the undesirable biological responses. These host-derived inflammatory mediators present new opportunities for developing treatment regimens against a wide variety of inflammatory disease states.
One of the most potent cytokines is cachectin, which is primarily released by macrophages after appropriate stimulation. Cachectin, also known as Tumor Necrosis Factor, is a protein having 157 amino acids normally found in vivo as a dimer or other multimer. The calculated molecular weight of human TNF monomer is about 17,000 daltons.
Cachectin acts to suppress biosynthesis of several adipocyte-specific proteins, such as lipoprotein lipase. It also acts to induce the biosynthesis or release of numerous other proteins, including Class I major histocompatibility antigen, granulocyte-macrophage-colony stimulating factor, and interleukin 1. (See, generally, Beutler and Cerami, New Eng. J. of Med., 316:379-385 (1987), which is incorporated herein by reference.)
The recognition of cachectin's broad influence on various disease states has led to attempts in controlling its actions. For example, experiments have shown that antibodies specifically reactive with cachectin may be therapeutically useful in controlling the immunomodulatory responses now known to be associated with cachectin (see, U.S. Pat. Nos. 4,603,106 and 4,684,623, both of which are incorporated herein by reference). In particular, neutralizing antibodies capable of binding various epitopes on human cachectin at high affinity have significant potential for mediating the toxic effects of excess cachectin levels.
Thus, there exists a need for improved antibodies capable of neutralizing the toxic effects of cachectin in vivo. The present invention fulfills these needs.